Ten Years of Progress in Renal Cell Carcinoma

In the past 10 years, much has changed in the management of advanced renal cell carcinoma (RCC; Figure 1). The treatment of early-stage disease has become less morbid, with the widespread adoption of robotic surgical techniques and the increased utility of thermal ablative techniques. For advanced disease, we have seen FDA approval of 7 new agents.17 Progress in sequencing technology and copy number analysis has resulted in the discovery of genes8,9 and chromosomal regions10,11 that may be responsible for disease development or progression. The lives of individuals with RCC are clearly better than they were at the beginning of the last decade. On the other hand, we still have much work to do. Unmet needs are found in the diagnosis and characterization of disease, in the choice of frontline systemic therapy, and in the decisions made at resistance. Much of the information obtained for RCC is focused on clear cell histology, and little is known about optimal treatment for variant histologies. In the next 10 years, we must better match therapy to patients and move from a histologically based to a molecularly based classification of disease.

With identification of the von Hippel-Lindau (VHL) gene12 and recognition that sporadic mutations of VHL are key drivers of clear cell RCC biology, an entirely new class of agents was developed to block the downstream consequences of hypoxia inducible factor upregulation and resultant vascular endothelial growth factor (VEGF) overproduction. Inhibitors of the VEGF ligand or VEGF receptor entered into clinical trials in the early 2000s. In December 2005, sorafenib became the first agent in this class to be FDA-approved for advanced RCC.6 A month later, sunitinib was also approved for the same indication.2 In the next 5 years, bevacizumab plus interferon (IFN) α,7 pazopanib,4 and axitinib5 were also approved.

Figure 1
Figure 1

Advances in the treatment of RCC, 2002–2012.

Abbreviations: IFN, interferon; OS, overall survival; RCC, renal cell carcinoma; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 10, 6; 10.6004/jnccn.2012.0071

Although individual studies have, for the most part, not shown a significant intra-study increase in overall survival (OS) for patients treated with antiangiogenic agents as frontline therapy, review of the 40% of patients in the upfront sunitinib versus IFN study who received no subsequent therapy shows a 28- versus 14-month OS, respectively.13 Additionally, large retrospective reviews of patient outcome after antiangiogenic therapy show a significant upward shift in OS for good- and intermediate-risk patient subgroups when compared with historical data from patients treated with immunotherapy.14

In the second-line setting, 2 agents are now FDA-approved. Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, showed a 4.9-month progression-free survival versus 1.9-months for placebo in patients who experienced progression on sorafenib, sunitinib, or both.1 More recently, axitinib, a highly selective VEGF receptor inhibitor, showed a 6.7-month progression-free survival in a mix of patients who had been treated with immunotherapy or VEGF receptor inhibitor, compared with 4.7 months for patients treated with sorafenib.5

Treatment of individuals with poor-risk features has also advanced in the past 10 years. A randomized phase III study comparing the mTOR inhibitor temsirolimus versus IFN showed a significant prolongation of OS in patients who received upfront temsirolimus.3 Although this improvement is modest, it speaks to an incremental and clinically important advancement in our ability to impact the natural history of advanced RCC, regardless of the initial presenting features.

Patients with advanced RCC clearly have more treatment options today than 10 years ago, and the literature includes statements about the current “embarrassment of riches” in the RCC therapeutic arena. Unfortunately, however, we have not won the battle. Resistance to existing therapies is an almost universal phenomenon, and we do not yet understand the mechanism behind its development. Despite advances in treatment, most patients with advanced disease still face a dramatically shorted life expectancy. An objective look at the therapeutic landscape shows development of only 2 classes of agents after an expenditure of billions of dollars and involvement of thousands of patients in clinical trials, with little to no effort expended on obtaining tissue and blood samples to understand the determinants of response and resistance.

The Next 10 Years

What is the path forward? Academia and industry must work together to develop molecularly based, personalized treatments. The following aims can help focus our attention on key goals.

Define the Best First-Line Therapy

We do not currently have a robust means of identifying individuals most likely to benefit from a particular therapy class or, more precisely, a specific agent. Prognostic algorithms like those based on the Heng14 and Memorial Sloan-Kettering15 criteria can be used to predict response and duration of response but are unlinked to any molecular signature or readout. A search for more robust clinical or tissue-based predictors has been underway for some time. Rini et al.16 recently published data showing that development of hypertension while on antiangiogenic therapy and prior history of hypertension were powerful predictors of treatment benefit and OS. Several mechanistic theories exist to explain this observation, but no human tissue–based confirmation exists.

Data from smaller phase II studies17 suggest that specific circulating factors can be used to predict treatment benefit and overall prognosis. The application of massively parallel sequencing technology8,9 and single nucleotide polymorphism–based copy number analyses10 in RCC allows the molecular characterization of tumors with unprecedented detail and ease. Conducting clinical trials in a way that will provide a robust mechanistic explanation for differential benefit from specific agents and classes of agents will be important. This goal can only be achieved by integrating the analysis of genomic, transcriptomic, and proteomic determinants with the capture of clinical outcomes. This is by nature an iterative process, because initial hypotheses must almost always be refined over time and over serial clinical studies.

Select Appropriate Subsequent Therapy

Duration of disease stabilization can vary considerably among individuals, and mechanisms of resistance may vary. Understanding how resistance develops and which agent to administer when it presents will require analysis of what changes occur in the tumor or in the tumor microenvironment as a function of treatment effect. Designing trials that permit these observations is critical, but the parallel development of tools that can accurately measure the relevant changes is of equal importance. Because metastatic disease is not easily accessible in most patients with RCC, performing biopsies is morbid, expensive, and may be subject to sampling error. A concerted effort must be made to improve the operating characteristics of biopsy analysis tools and ensure a thorough understanding of their utility.

With these tools, we must examine the alterations in the tumor epithelial, endothelial, and stromal compartments as a function of therapy. Trial designs that permit acquisition of useful material include presurgical and sequential studies. The former can acquire nephrectomy specimens that have undergone changes as a function of treatment, and these changes can be linked to clinical outcome. Although the results are a signature of primary refractoriness, the information can provide valuable insight into what may be occurring in cases of acquired resistance. Sequential studies can then be used to evaluate tissue and circulating factors at the time of primary resistance and assess which second-line agent is efficacious in that specific context.

Discover New Targets

Clearly, the currently available agents cannot eradicate RCC. Despite developing compounds with picomolar VEGF receptor inhibitory capabilities, we have not seen an increase in cure fraction beyond a handful of patients. A closer look at the mechanism of action of currently available agents explains why. Antiangiogenic agents, by definition, target the tumor endothelium and are not cytocidal against the epithelial tumor cell. Blockade of TORC1, the key effect of the current generation of rapamycin-based mTOR inhibitors, is cytostatic. Some preclinical work has been performed to identify compounds that induce “synthetic lethality” in VHL-deficient cells. However, more work is needed to identify a potential “Achilles’ heel” in clear cell and non–clear cell RCC.

An alternate strategy is to rescue the function of mutated protein, thereby altering the tumor phenotype in RCC cells. Recent work with combined VEGF receptor and MET inhibitors shows promise as well, and determining which patients will benefit from this treatment will be important. A renaissance in immunotherapy is occurring. Antibodies targeting T-cell regulatory receptors are approved for melanoma and are in clinical trials for RCC. These agents provide hope that harnessing one of the body’s most powerful regulatory systems may finally be consistently useful to patients with advanced RCC.

Conclusions

A great deal of progress has been made in the treatment of RCC in the past 10 years. We now have treatments that impact tumor biology in a consistent fashion, and tools are available with which we can measure effect. We must now use these resources to match treatments to patients and develop novel therapies and strategies that can actually cure RCC.

References

  • 1

    MotzerRJEscudierBOudardS. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet2008;372:449456.

    • Search Google Scholar
    • Export Citation
  • 2

    MotzerRJHutsonTETomczakP. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med2007;356:115124.

  • 3

    HudesGCarducciMTomczakP. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med2007;356:22712281.

  • 4

    SternbergCNDavisIDMardiakJ. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol2010;28:10611068.

    • Search Google Scholar
    • Export Citation
  • 5

    RiniBIEscudierBTomczakP. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet2012;378:19311939.

    • Search Google Scholar
    • Export Citation
  • 6

    EscudierBEisenTStadlerWM. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med2007;356:125134.

  • 7

    EscudierBPluzanskaAKoralewskiP. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet2007;370:21032111.

    • Search Google Scholar
    • Export Citation
  • 8

    VarelaITarpeyPRaineK. Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature2011;469:539542.

    • Search Google Scholar
    • Export Citation
  • 9

    DalglieshGLFurgeKGreenmanC. Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature2010;463:360363.

    • Search Google Scholar
    • Export Citation
  • 10

    MonzonFAAlvarezKPetersonL. Chromosome 14q loss defines a molecular subtype of clear-cell renal cell carcinoma associated with poor prognosis. Mod Pathol2011;24:14701479.

    • Search Google Scholar
    • Export Citation
  • 11

    KlatteTRaoPNde MartinoM. Cytogenetic profile predicts prognosis of patients with clear cell renal cell carcinoma. J Clin Oncol2009;27:746753.

    • Search Google Scholar
    • Export Citation
  • 12

    LatifFToryKGnarraJ. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science1993;260:13171320.

  • 13

    FiglinRAHutsonTETomczakP. Overall survival with sunitinib versus interferon (IFN)-alfa as first-line treatment of metastatic renal cell carcinoma (mRCC) [abstract]. J Clin Oncol2008;26(Suppl):Abstract 5024.

    • Search Google Scholar
    • Export Citation
  • 14

    HengDYXieWReganMM. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study. J Clin Oncol2009;27:57945799.

    • Search Google Scholar
    • Export Citation
  • 15

    MotzerRJBacikJMurphyBA. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol2002;20:289296.

    • Search Google Scholar
    • Export Citation
  • 16

    RiniBICohenDPLuDR. Hypertension as a biomarker of efficacy in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst2011;103:763773.

    • Search Google Scholar
    • Export Citation
  • 17

    ZuritaAJJonaschEWangX. A cytokine and angiogenic factor (CAF) analysis in plasma for selection of sorafenib therapy in patients with metastatic renal cell carcinoma. Ann Oncol2012;23:4652.

    • Search Google Scholar
    • Export Citation

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Eric Jonasch, MD, is Associate Professor in the Department of Genitourinary Medicine at The University of Texas MD Anderson Cancer Center. He completed his medical education at McGill University in Montreal, Canada, and his fellowship at the Beth Israel Deaconess Medical Center. Dr. Jonasch is board certified in medical oncology, hematology, and internal medicine by the American Board of Internal Medicine, and in oncology and medicine by the Royal College of Physicians & Surgeons of Canada. His professional memberships include the American Association for Cancer Research and ASCO. He is a member of the NCCN Guidelines Panel for Kidney and Testicular Cancers. Dr. Jonasch is also a medical advisor for the Kidney Cancer Association and the von Hippel-Lindau Family Alliance.

Dr. Jonasch has authored more than 80 peer-reviewed articles, several book chapters, and a textbook on kidney cancer, and has presented at numerous national and international conferences.

Dr. Jonasch’s research interests include renal cell carcinoma, von Hippel-Lindau disease, and defining the determinants of response and resistance to antiangiogenic agents. He is principal investigator of a National Institutes of Health Roadmap initiative grant, and several industry and institutionally sponsored research grants.

Robert J. Motzer, MD, is a medical oncologist at Memorial Sloan-Kettering Cancer Center, with a primary area of expertise in kidney (renal cell carcinoma) and testicular cancer (germ-cell tumor), and has led more than 50 clinical trials for these cancers both nationally and internationally. Through this research, he helped identify 3 targeted antiangiogenesis drugs that serve as effective first- or second-line treatments for patients with advanced kidney cancer. Dr. Motzer helped develop a system to aid in predicting outcomes for patients taking medications for advanced kidney cancer—a tool now widely applied by physicians around the world to direct the care of patients.

In addition to publishing more than 300 original articles, scientific reviews, chapters, and abstracts, Dr. Motzer has lectured on kidney and testicular cancer care internationally and worked to improve cancer care through health care policy and advocacy activities. Dr. Motzer chairs the NCCN Guidelines Panels for Kidney and Testicular Cancers.

Dr. Motzer graduated from the University of Michigan Medical School and has received the Career Development Award from the NIH and the Willet F. Whitmore Award for Clinical Excellence from Memorial Sloan-Kettering.

The ideas and viewpoints expressed in this editorial are those of the author and do not necessarily represent any policy, position, or program of NCCN.

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    Advances in the treatment of RCC, 2002–2012.

    Abbreviations: IFN, interferon; OS, overall survival; RCC, renal cell carcinoma; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor.

References

  • 1

    MotzerRJEscudierBOudardS. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet2008;372:449456.

    • Search Google Scholar
    • Export Citation
  • 2

    MotzerRJHutsonTETomczakP. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med2007;356:115124.

  • 3

    HudesGCarducciMTomczakP. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med2007;356:22712281.

  • 4

    SternbergCNDavisIDMardiakJ. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol2010;28:10611068.

    • Search Google Scholar
    • Export Citation
  • 5

    RiniBIEscudierBTomczakP. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet2012;378:19311939.

    • Search Google Scholar
    • Export Citation
  • 6

    EscudierBEisenTStadlerWM. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med2007;356:125134.

  • 7

    EscudierBPluzanskaAKoralewskiP. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet2007;370:21032111.

    • Search Google Scholar
    • Export Citation
  • 8

    VarelaITarpeyPRaineK. Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature2011;469:539542.

    • Search Google Scholar
    • Export Citation
  • 9

    DalglieshGLFurgeKGreenmanC. Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature2010;463:360363.

    • Search Google Scholar
    • Export Citation
  • 10

    MonzonFAAlvarezKPetersonL. Chromosome 14q loss defines a molecular subtype of clear-cell renal cell carcinoma associated with poor prognosis. Mod Pathol2011;24:14701479.

    • Search Google Scholar
    • Export Citation
  • 11

    KlatteTRaoPNde MartinoM. Cytogenetic profile predicts prognosis of patients with clear cell renal cell carcinoma. J Clin Oncol2009;27:746753.

    • Search Google Scholar
    • Export Citation
  • 12

    LatifFToryKGnarraJ. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science1993;260:13171320.

  • 13

    FiglinRAHutsonTETomczakP. Overall survival with sunitinib versus interferon (IFN)-alfa as first-line treatment of metastatic renal cell carcinoma (mRCC) [abstract]. J Clin Oncol2008;26(Suppl):Abstract 5024.

    • Search Google Scholar
    • Export Citation
  • 14

    HengDYXieWReganMM. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study. J Clin Oncol2009;27:57945799.

    • Search Google Scholar
    • Export Citation
  • 15

    MotzerRJBacikJMurphyBA. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol2002;20:289296.

    • Search Google Scholar
    • Export Citation
  • 16

    RiniBICohenDPLuDR. Hypertension as a biomarker of efficacy in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst2011;103:763773.

    • Search Google Scholar
    • Export Citation
  • 17

    ZuritaAJJonaschEWangX. A cytokine and angiogenic factor (CAF) analysis in plasma for selection of sorafenib therapy in patients with metastatic renal cell carcinoma. Ann Oncol2012;23:4652.

    • Search Google Scholar
    • Export Citation

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